GABAA receptor agonist

A GABA_A receptor agonist is a drug that acts as an orthosteric agonist of the GABA_A receptor, the major signaling receptor of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).^[1][2][3]

Not to be confused with GABAA receptor positive allosteric modulator.

GABAA receptor agonist
Drug class
Gaboxadol (THIP), a well-known GABAA receptor agonist and hypnotic.
Class identifiers
Synonyms	GABAA agonist
Use	Seizures, insomnia, hallucinogenic effects
Mechanism of action	GABAA receptor agonism
Biological target	GABAA receptor
Chemical class	GABA analogues and others
Legal status

The mechanism of action of GABA_A receptor agonists is unlike that of GABA_A positive allosteric modulators, including benzodiazepines, Z drugs, barbiturates, neurosteroids, and alcohol, which instead act via allosteric regulatory sites to potentiate GABA_A receptor function.^[4][3] GABA_A receptor agonists have different effects from those of GABA_A receptor positive allosteric modulators.^[5][6][7][8]

Examples of GABA_A receptor agonists include GABA itself, γ-amino-β-hydroxybutyric acid (GABOB), muscimol (found in Amanita muscaria mushrooms), gaboxadol (THIP), and progabide, among others.^[1][2][3] High-efficacy GABA_A receptor agonists have been found to produce sedative, hypnotic, anticonvulsant, and hallucinogenic effects, among others.^{[9][10][11][12]} The structural requirements for GABA_A receptor binding and activation have been found to be very strict, so relatively few high-efficacy GABA_A receptor agonists are known.^[2][13] No fully selecive GABA_A receptor agonists, for instance lacking any additional activity at the closely related GABA_A-ρ and/or GABA_B receptors, are currently known.^[14]

GABA_A receptor agonists are generally GABA analogues and derivatives.^[1][2] Muscimol, a conformationally restrained analogue of GABA, was among the first GABA_A receptor agonists to be identified.^[15]

GABA

Main article: γ-Aminobutyric acid

Chemical structure of γ-aminobutyric acid (GABA).

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system.^[6][16][17] It is present in about 25 to 50% of neurons in the brain.^[17] The neurotransmitter acts as a non-selective agonist of all three types of GABA receptors, including the GABA_A receptor, GABA_B receptor, and GABA_A-rho receptor (GABA_C receptor).^[6][16] GABA is available as an over-the-counter supplement and is often taken for self-treatment of insomnia and anxiety.^[18][19] However, GABA is highly susceptible to metabolism, has a very short elimination half-life, and is unable to cross the blood–brain barrier.^[18][19] As such, the therapeutic benefits of exogenous GABA are questionable.^[19]

GABOB

Main article: γ-Amino-β-hydroxybutyric acid

Chemical structure of γ-amino-β-hydroxybutyric acid (GABOB; Gamibetal).

γ-Amino-β-hydroxybutyric acid (GABOB) is a close endogenous analogue of GABA found in the human brain.^[20] It acts as a dual GABA_A and GABA_B receptor agonist.^[21] The drug has anticonvulsant effects and has been used in the treatment of epilepsy under brand names like Gamibetal in some countries throughout the world.^[22][20][23]

Muscimol

Main article: Muscimol

Chemical structure of muscimol, found in Amanita muscaria.

Amanita muscaria (fly agaric) mushrooms, which contain muscimol.

Muscimol is an alkaloid found in Amanita mushrooms such as Amanita muscaria (fly agaric).^[10][15][24] It is a conformationally constrained derivative of GABA.^[15][25] The drug is a highly potent GABA_A receptor full agonist.^[10][15] However, it is a selective or preferential agonist of extrasynaptic δ subunit-containing GABA_A receptors.^[10][26][27] The drug also acts as a potent GABA_A-ρ receptor partial agonist and weak GABA reuptake inhibitor.^[10][15][25] Muscimol is a sedative and hallucinogen.^[10][28][29] Ibotenic acid, another alkaloid found in Amanita mushrooms, is a neurotoxin but functions as a prodrug of muscimol and has similar effects.^[30][28][25] Muscimol has served as the base structure for development of many synthetic GABA system modulators, including GABA receptor modulators and GABA reuptake inhibitors.^[5][31] The compound has been used recreationally as a hallucinogen and has become increasingly used at low doses for claimed therapeutic benefits, such as sleep improvement.^{[10][32][33][34]}

Gaboxadol

Main article: Gaboxadol

Chemical structure of gaboxadol (THIP).

Gaboxadol (THIP) is a synthetic derivative of muscimol which acts as a potent GABA_A receptor partial agonist.^[7][8][11] However, it is a selective or preferential supramaximal agonist of extrasynaptic δ subunit-containing GABA_A receptors.^[2][7][9] The drug is also a potent GABA_A-ρ receptor antagonist.^[14] Gaboxadol has improved selectivy and drug-like properties compared to muscimol.^{[7][15][5][11]} It has sedative, hypnotic, and, at high doses, hallucinogenic effects.^[8][2][11] The drug was developed for treatment of insomnia and other conditions.^[8][2][11] It was found to be effective in the treatment of insomnia, with advantageous properties compared to other hypnotics, such as increased slow wave sleep (deep sleep).^[8][2][35] Gaboxadol completed phase 3 clinical trials for this indication.^[36] However, it was discontinued for various reasons, most notably a narrow therapeutic index with high rates of hallucinogenic effects at supratherapeutic doses.^[37][38][39]

Progabide

Main article: Progabide

Chemical structure of progabide (Gabrene).

Progabide is a GABA derivative which acts as a dual GABA_A and GABA_B receptor agonist.^{[12][40][41][42]} It produces the more potent GABA receptor agonist progabide acid (SL-75102) as an active metabolite and is additionally a prodrug of gabamide and GABA.^{[12][41][43][42]} The drug is used as an anticonvulsant under the brand name Gabrene in France.^[44] The use of progabide has been limited by poor clinical effectiveness and incidence of liver toxicity.^[45]

Picamilon

Main article: Picamilon

Chemical structure of picamilon (N-nicotinoyl-GABA).

Picamilon (N-nicotinoyl-GABA) is a GABA analogue, specifically a conjugate of GABA and nicotinic acid (niacin), which is used as a pharmaceutical drug and vasodilator in Russia for various indications.^[46][47] In addition, it has emerged in supplements elsewhere in the world and is advertised and used as a purported nootropic (cognitive enhancer).^[46][48] The drug crosses the blood–brain barrier and is hydrolyzed into GABA and nicotinic acid in animals, and hence is assumed to act as a centrally active and metabolism-resistant prodrug of these metabolites.^[46][49] Picamilon itself has been found to be inactive at a large panel of targets, including the GABA receptors, GABA transporters, GABA transaminase, and calcium channels, which are all known targets for other GABA analogues.^[46] The drug is relatively little-researched.^[46]

Others

Other GABA_A receptor agonists include 4-AHP,^[50] dihydromuscimol, imidazole-4-acetic acid (IAA, IMA), isoguvacine, isonipecotic acid, methylglyoxal,^[51] nefiracetam (DM-9384),^[52] 4-PIOL, piperidine-4-sulfonic acid (P4S), quisqualamine,^[53][54][55] thiomuscimol, and tolgabide (SL-81.0142), among others.^[56][6][57] Some of these compounds, such as isoguvacine, isonipecotic acid, and P4S, are known to be unable to cross the blood–brain barrier.^[58][7][59]

Indirect agonists

Main articles: GABA reuptake inhibitor and GABA transaminase inhibitor

Indirect agonists of the GABA_A receptor, as well as of the other GABA receptors, include GABA reuptake inhibitors like the anticonvulsant tiagabine (Gabitril) and GABA transaminase (GABA-T) inhibitors like the anticonvulsant vigabatrin (Sabril).^{[60][61][62][63]}

See also

• GABA receptor agonist
• GABA_A receptor positive allosteric modulator